Cognitive impairment is a serious neurological condition which is very common in the elderly. It is estimated that approximately one-third of people who live to be over 80 years of age will be diagnosed with some form of cognitive impairment, or dementia. Cognitive impairment can result from a variety of disease processes, such as, but not limited to:
Neurodegenerative dementia:                Alzheimer's Disease        Pick's Disease        Progressive Supranuclear Palsy        Dementia with Lewy Bodies        Parkinson's Disease        Fronto-temporal Dementia        
Vasular Diseases:                Stroke        Multi-infarct dementia        Subarachnoid hemorrhage        
Head Trauma
Infections:                Post-encephalitic dementia        Syphilis        Herpetic encephalitis        
Congenital abnormalities:                Trisomy 21        
Toxic Brain Injuries:                Wernike Encephalopathy        Krorsakoff psychosis        Alcoholic amnesic syndrome        Alcoholic dementia        
The primary result of this general condition is a universal decline in the intellectual function of the individual, usually resulting in significant impediments to normal daily functions. While there is currently no disease modifying therapy available for most forms of cognitive impairment, certain therapies are available to improve cognitive functioning to varying degrees which can alleviate or at least delay the need for institutionalizing these individuals.
It has been determined that the decline of the neurotransmitter chemical acetylcholine in the brain is one of the primary mechanisms of declining mental function. Medications that can prevent or at least minimize the breakdown of acetylcholine in the brain provide significant improvement in the cognitive abilities of patients diagnosed with cognitive impairment. These medications are commonly referred to as acetyl-cholinesterase inhibitors. However, as with any medication, there are side effects. Acetyl-cholinesterase inhibitors exacerbate urinary and fecal incontinence in patients administered these drugs. Other side effects include a reduced heart rate, sweating, vasodilation and increased bronchial secretions. Such side effects may be so uncomfortable for many elderly patients that the patient is unable to tolerate effective dosing of acetyl-cholinesterase inhibitors to successfully treat the cognitive impairment.
Attempts to ameliorate these undesirable side effects in cognitively impaired patients include the administration of, for example, antimuscarinic-anticholinergic drugs (commonly called “anti-muscarinics”). These drugs block the peripheral stimulation of the acetylcholine receptors. Unfortunately, however, the use of these medications to treat the side effects of acetyl-cholinesterase inhibitors mentioned previously often contribute to cognitive impairment that is being treated. Thus, benefits of using these drugs must be balanced with the risks of exacerbating the existing cognitive impairment. As a result, many patients are either inadequately treated or go untreated.
In addition to cognitive impairment, a more severe problem often afflicts the elderly and is referred to as acute delirium. The primary indicators are a pronounced change in mental status that rapidly fluctuates, the inability to maintain normal degrees of attention, disorganized thinking and vacillating levels of consciousness. Acute delirium can often result from a severe medical illness, recent surgery and several medications or interactions between various medications. The impact of acute delirium on patients is severe and often chronic, frequently leading to death.
While the neurological mechanism by which acute delirium occurs is not completely understood, like cognitive impairment, the neurotransmitter acetylcholine is thought to play a significant role. In patients suffering from dementia, a decline in acetylcholine has been seen in post mortem studies. As with treatments for cognitive impairment, the use of acetyl-cholinesterase inhibiting medications has been determined to prevent, to varying degrees, the breakdown of acetylcholine in the brain. However, the undesired side effects outside the central nervous system that have been discussed above often result. In order to minimize these problems, the administration of drugs that block the peripheral effects of acetylcholinesterase inhibitors act would be desirable. Unfortunately, in a manner similar to other cognitive impairments, anticholinergics frequently contribute to the underlying problem by causing central nervous system toxicity.
There is thus a severe need to treat patients suffering from various forms of cognitive impairment as well as those suffering from acute delirium with an effective amount of medication to minimize or entirely alleviate these conditions without imposing upon them the undesired peripheral effects discussed previously, especially urinary and/or fecal incontinence, nausea, bradychardia, bronchorrhea and/or bronchospasm which often coexist with these cognitive impairments. The desire is to be able to administer the most efficacious type and amount of medication to treat the neurological condition without increasing the unwanted side effects of high doses of those medications. This balance has yet to be achieved in modern clinical practice.
It has been recognized that in patients suffering from incontinence, acetyl-cholinesterase inhibitors can “increase the tone of the external sphincter” (U.S. Pat. No. 5,861,431, Hildebrand et al., issued Jan. 19, 1999). The patentees note that compounds such as glycopyrrolate directly inhibit acetylcholine receptors in the bladder wall, which reduces the excessive stimulation of the bladder caused by nerves which are no longer inhibited by a normal central nervous system. Commonly assigned U.S. Pat. Nos. 6,204,285 and 6,063,808 describe the use of a single enantiomer of glycopyrrolate to treat patients suffering from urinary incontinence. They teach away from a racemic mixture of this molecule. They note that approximately 15-30% of elderly people are afflicted by urinary incontinence, but do not connect the cause of incontinence with treatments for either cognitive disorders or acute dementia.